<p>Corneal transplant rejection poses a significant challenge for patients undergoing high-risk penetrating keratoplasty (HR-PKP). We systematically reviewed the literature to evaluate the efficacy of combining topical tacrolimus with steroids in reducing graft failure rates. A systematic review and meta-analysis were conducted according to PRISMA guidelines. PubMed, Web of Science and CENTRAL/Cochrane databases were searched from inception to September 2024. Meta-analyses were conducted using weighted means, proportions and log odds ratios (OR) with a random-effects model. A two-tailed p-value of &lt;0.05 was considered statistically significant. Out of 653 articles identified initially, five homogeneous comparative studies (n = 274 HR-PKP patients) were included. The tacrolimus-plus-steroids (n = 138) and steroids-alone (n = 136) groups were well-matched in baseline characteristics: weighted mean age (54.0 vs. 52.6 years, p = 0.90), sex distribution (p = 0.68), and underlying diagnoses with keratoconus being the most common (29.7% vs. 25.6%, p = 0.68). Follow-up durations were comparable as well (20.1 vs. 20.2 months, p = 0.98). After undergoing HR-PKP, patients in the tacrolimus-plus-steroids group showed significantly reduced graft failure odds by 75.0% (OR: 0.25 [95% CI: 0.13–0.43]) compared to patients in the steroids-alone group (p = 0.01). While preserving graft viability in HR-PKP patients remains challenging, adjunctive topical tacrolimus combined with steroids demonstrates a clinically meaningful reduction in graft failure risk. Larger long-term studies are warranted to validate these findings.</p>